: There is a need for early molecular indicators of the efficacy of chemoprevention and of interindividual variation in potential risk reduciton. A double-blind, placebo-controlled intervention trial is proposed using biologic markers to evaluate whether supplementation with antioxidant micronutrients reduces DNA damage in a cohort of 300 cigarette smokers and whether genetic factors modulate the effects of the micronutrients. Study subjects will be recruited through the New York State Psychiatric Institute and will be randomized into placebo or vitamin treatment groups. The latter will receive 400 IU vitamin E, and 500 mg vitamin C, based on experimental and epidemiologic evidence that these micronutrients inhibit DNA damage and tumor formation. Biomarkers of DNA damage and plasma vitamin levels will be evaluated in blood sample drawn at baseline and at three month intervals over one year of treatment and one year of follow-up. Buccal cells will be stored for future analyses. The study will address three specific issues: 1) whether suppplementation reduces smoking-induced DNA damage (aromatic-DNA adducts and oxidative DNA damage, including 8-hydorxydeoxyguanine and 5-hydroxymethyl-2'deoxyuridine in peripheral mononuclear cells); 2) whether DNA damage increases significantly after cessation fo vitamin supplementation; and 3) whether genetic susceptibility factors (glutathione-S-transferase M1 deletion and CYHP1A1 polymorphisms) modulate the relationship between DNA damage and antioxidant micronutrients. This type of validation study is a prerequisite to incorporating markers of DNA damage and plasma micronutrients into large-scale, long-term intervention studies designed to look at reduction of cancer incidence in smokers and ex-smokers. Once validated in this model population, these biomarkers would also have applicability in evaluating interventions in occupational cohorts and other populations highly exposed to carcinogens.